Systematic Study of Non-Natural Short Cationic Lipopeptides as Novel Broad-Spectrum Antimicrobial Agents

We describe the design and synthesis of a new series of non-natural short cationic lipopeptides (M-W=700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as Gram-positive, Gram-negative bacteria, fungi including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP16 possesses broad-spectrum antimicrobial activity and has MICs in the range of 1.5-6.25g/mL against Escherichia coli, S.aureus, Pseudomonas aeruginosa, Bacillus subtilis, and MRSE. All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells (HC50>250g/mL). Moreover, most potent lipopeptides (LP16 and LP23) did not induce drug resistance in S.aureus even after 15 rounds of passaging. In addition, a representative lipopeptide (LP16) showed tryptic stability for 24h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics.